Diabetes mellitus is a syndrome characterized by abnormal insulin secretion associated with fasting hyperglycemia and decreased glucose tolerance. A National Diabetes Data Group (NDDG) of the National Institutes of Health distinguishes five subclasses of diabetes. These include insulin-dependent diabetes mellitus (Type I), a ketosis-prone type of diabetes associated with histocompatibility antigens on chromosome 6 and with islet cell antibodies, and non-insulin-dependent diabetes mellitus (Type II), a non-ketosis-prone type of diabetes not secondary to other diseases or conditions. Type II diabetes is characterized by tissue insensitivity or resistance to insulin and impaired pancreatic B cell response to glucose. (Karam, J. H., in Basic Clinical Pharmacology, 5th Ed., B. G. Katzung, ed, Appleton & Lange, Norwalk, Conn., 1992, pp. 586-601).
The accepted treatment of diabetes mellitus is generally insulin replacement by insulin injection, insulin pump, and the like. The objectives of the treatment are to avoid ketoacidosis and to control symptoms resulting from hyperglycemia and glucosuria.
Chronic treatment with insulin, especially in Type II diabetes mellitus, or the endogenous production of high levels of insulin in many cases results in the development of insulin resistance. Current therapy for treatment of insulin resistance is injection of high doses of insulin to provide greater availability to insulin receptors in the tissues. Very high doses of insulin may ultimately be required, and the resulting high circulating levels of insulin cause some of the side effects associated with insulin resistance such as diabetic nephropathy. This "therapy" may in fact worsen the disease.
Sulfonylurea drugs may be administered as hypoglycemic agents (Katzung B. G., in Basic and Clinical Pharmacology, 5th Ed., 1992, p. 585-597), however, these sulfonylurea drugs are effective in overcoming insulin resistance only in a small population of patients (approximately 30%) (Groop, L. C., Diabetes Care, 15:737-754, 1992; Groop and Pelkonen, Acta Endocrinol. Suppl. 262:131-135, 1984).
Biguanide drugs, while not used in this country, are being tested in clinical trials as hypoglycemic agents (Katzung p. 598-599). Likewise, pioglitazone is being tested in clinical trials as a hypoglycemic agent (Hoffman and Colca, Diabetes Care, 15:1075-1078, 1992; Koybayashi et al., Diabetes, 41:476-483, 1992. Although these agents are being tested to evaluate usefulness in decreasing insulin resistance, no mechanism has been described to explain how they exert their effects. As has been found with sulfonylureas, the bignanides and pioglitazone may be found to be ineffective in a large percentage of patients, or the effectiveness of the agents may decline with longterm use. New therapeautic agents to decrease insulin resistance need to be identified and brought to clinical practice. To date in the U.S.A., no therapeutic agent is available for clinical use to reduce or eliminate insulin resistance.
The inventors have recently discovered that chronic treatment of cultured cells with high concentrations of insulin, conditions which mimic the hyperinsulinemic state of Type II diabetes mellitus, resulted in the generation of a cytosolic fragment of the insulin receptor, termed .beta.'. These studies also showed that the irreversible thiol protease inhibitor, E-64, inhibited the production of the insulin receptor fragment .beta.'. (V. P. Knutson, The Journal of Biological Chemistry, 266:15656-15652, Aug. 25, 1991.) Co-incubation of partially purified, intact insulin receptor with increasing concentrations of the .beta.' fragment led to the dose-dependent inhibition of insulin-induced receptor autophosphorylation, the first step in the insulin signal transduction cascade. Without wishing to be bound by theory, it is hypothesized that the .beta.' fragment, by inhibiting insulin signal transduction, may mediate insulin resistance. It would therefore be highly desirable to provide a pharmaceutically acceptable agent which would effectively reduce the levels of the insulin receptor .beta.' fragment in diabetic patients, and thereby reduce or eliminate insulin resistance.